The consumption of alcohol during adolescence and young adulthood is a serious public health problem. In this age group, alcohol is often consumed in large quantities in repeated binge-like episodes that result in serve levels of intoxication. In addition to legal ramifications and concerns with physical safety, these patterns of alcohol consumption appear to adversely impact continued neuromaturation during the transition from adolescence to adulthood. The prefrontal cortex (PFC) controls higher-order cognitive functions such as working-memory, behavioral flexibility, and impulse control (collectively referred to as executive cognitive function). Adolescence represents a critical period of refinement of the neurocircuitry of the PFC that supports maturation of executive cognitive functioning. Deficits in executive cognitive function are associated with loss of control over behavioral processes such as attention and emotion, and with increased engagement in risky behaviors such as unprotected sex and drug-taking. The latter includes a reduced ability to discontinue drug-taking once initiated resulting in escalation in, and loss of control over, consumption. The overarching hypothesis of this research component of the NADIA consortium is that repeated binge-like exposure to alcohol during adolescence produces a neuropathology of the PFC that manifests in the adult as deficits in executive cognitive function and behavioral control. This hypothesis will be tested by an innovative and multidisciplinary set of experiments that utilize state-of the- art methodologies and procedures in a rat model of adolescent intermittent ethanol (AIE) exposure. The overarching hypothesis will be tested by four specific aims that will: 1) Determine the effects of AIE exposure on epigenetic modifications (histone acetylation) in identified populations of excitatory pyramidal and inhibitory interneurons in the medial PFC and dopamine (DA) projection neurons in the ventral tegmental area;2) Determine the effects of AIE exposure upon DA modulation of excitatory pyramidal and inhibitory GABAergic interneurons in the adult medial PFC;3) Determine the effects of AIE exposure and re-exposure to alcohol during adulthood on executive cognitive function using tasks that assess working memory, behavioral flexibility, and risk-taking behavior;and 4) Assess the effects of AIE exposure and reexposure to alcohol during adulthood on cognitively modulated synchronous activity and organization of neuronal ensembles in the mPFC. Together, these studies will yield novel and exciting new finding and will significantly advance our understanding of the effect of adolescent alcohol exposure on cognitive function and behavioral control in the adult. PUBLIC HEALTH RELEVANCE: Binge-like consumption of alcohol during adolescence is common and represents a serious public health concern. Adolescence represents a critical period of development of cortical processes that underlie maturation of behavioral control and decision-making. Thus, studies examining how adolescence alcohol consumption results in deficits in these cortical processes that persist well into adulthood are highly significant.